Peroxisome proliferator-activated receptors (PPARs) are a nuclear receptor superfamily comprised of PPAR alpha, beta, and gamma. PPARs have been identified in the ovary of rats, cows, and humans, but very little is known about the function of these factors in ovarian physiology. PPAR gamma has been shown to play a role in angiogenesis, inflammation, cell differentiation, and steroidogenesis. Because these are crucial processes in ovarian function, the applicant hypothesizes that PPARs play a role in ovarian follicular and luteal development, as well as steroidogenesis. She has preliminary data showing that PPAR gamma expression is restricted to granulosa cells and is down regulated by the gonadotropin surge. Specific Aim 1 will characterize the type of follicles expressing PPAR gamma by looking at markers for follicular differentiation (P450 aromatase and the gonadotropin receptors), luteinization (P450 side-chain cleavage and cyclooxygenase-2), and apoptosis, in conjuction with PPAR gamma. She also has preliminary data from cultured rat granulosa cells demonstrating that inhibiting the activity of PPAR gamma resulted in a doubling of gonadotropin- stimulated progesterone production. The experiments outlined in Specific Aim 2 will further investigate the role of PPAR gamma in steroidogenesis both in vitro and in vivo by using specific agonists and an antagonist for PPAR gamma and measuring the expression of P450 aromatase and P450 side-chain cleavage. Because of the observed decrease in expression of PPAR gamma after the gonadotropin surge, Specific Aim 3 will address the role of protein kinases A and C, second messenger systems activated by LH, in regulating the expression of PPAR gamma. The data generated by these experiments will elucidate the role(s) of PPARs in ovarian cyclicity. Because drugs that are known to activate PPARs, thiazolidinediones (a class of drugs used to treat hyperinsulinemia) and fibrates ( drugs used to treat hyperlipidemia) are activators of PPARs, these studies will also provide timely information about how these drugs may impact ovarian physiology.